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D. Morarescu, J. A. West-Mays, H. Sheardown; MMP Inhibitors Released From PDMS for Mitigating Secondary Cataracts. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2771.
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Matrix metalloprotease inhibitor (MMPI) treatment of TGF-β2 activated lens explants has been shown to completely mitigate the formation of anterior subcapsular cataracts. Since PCO is the result of a similar transformation in equatorial lens bow cells, we hypothesize that treatment with MMPIs may improve the long term success of intraocular lens (IOL) devices. The release of 7 MMPIs, including broad range and specific MMP-2 and MMP-9 inhibitors, chelators and antibiotics from PDMS as a model IOL material has been investigated.
PDMS sheets were prepared from Sylgard 184 (Dow Corning). MMPI loaded materials were made by adding a solution of inhibitor in DMF or ethanol, to elastomer base. Disks of ¼" diameter were incubated in PBS or TBS, pH 7.4, at 37°C with mild agitation for release. MMPI concentration was measured by UV absorbance. Inhibitor activity was tested in vitro by incubating 1.6 ng MMP-9 active enzyme (Calbiochem), with a fluorescent substrate. Toxicity of the drugs was tested in tissue culture using: B3 human lens epithelials (B3 HLE), FHL124 human lens epithelials, human corneal stromal fibroblasts (HCSF), human corneal epithelials (HCE), human retinal pigment epithelials (RPE). Inhibitors were added to complete media, two days after cells were seeded. Cell viability was measured by MTT assay.
There was minimal toxicity of the MMPIs at 1 and 5 days with any cell type other than lens epithelials based on both cell counts and MTT assay. Inhibitor release for periods of 4-6 months was observed depending on formulation. Released inhibitors were found to maintain sufficient activity after release to presumably inhibit the amount of MMPs in the human capsule, for up to 5 months in some cases. Further studies are necessary to examine the effect of these molecules on markers of cataract formation.
Seven MMP inhibitors have been successfully loaded and steadily released in active form from PDMS as a model IOL material, at concentrations similar to those that have been previously shown to inhibit MMP activity in the lens capsule. Toxicity analysis via MTT assay demonstrated that these compounds are harmless to lens epithelial cells and other ocular cell types at very high concentrations. This model presents a promising way to mitigate PCO via a modified PDMS based IOL material.
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